Head and neck squamous cell carcinoma (HNSCC) remains a devastating disease with significant morbidity related to the tumor and to aggressive treatment. Current staging methods are inadequate to predict which patients are at risk and are in need of aggressive therapy; therefore patients at low risk are frequently subjected to morbidity of unnecessary therapy. The best predictor of outcome in HNSCC remains the presence or absence of neck metastases. Attempts to augment the predictive power of the clinical staging system through use of molecular analyses have proven unfruitful because of low predictive accuracy and conflicting results when individual gene defects or expressions were examined. Emerging technologies have made possible the examination of the expression of large numbers of genes within tumor samples. This data has been very useful in predicting aggressiveness and/or metastases of breast cancers, lung cancers and other epithelial and nonepithelial tumors. Using gene array technology, we propose to determine gene expression profiles in HNSCC that predict the presence or absence of metastases. Success of this technique will allow aggressive treatment of tumors at high risk of metastases, while patients at low risk are spared morbidity associated with aggressive therapies. Since neck metastases of HNSCC correlates with survival, these markers may also predict survival.